Neuropeptide Y (NPY) is a highly bioactive 36-amino acid peptide that occurs abundantly in brain. In preliminary experiments, we found that repeated administration of cocaine elicits substantial, long-lasting, biochemically-selective, and reversible reductions in levels of NPY and NPY mRNA in regions of rat cerebral cortex and nucleus accumbens. Excitotoxic lesions of medial prefrontal cortex, a region thought to be of importance for the expression of some of cocaine's reinforcing properties, did not affect NPY per se but prevented the reduction of NPY elicited by cocaine. Thus, it appears that chronic exposure to cocaine transneuronally reduces, in selected neurons, the biosynthesis of NPY, possibly in response to increases in synaptic dopamine (DA) deriving from mesolimbic/mesocortical neurons; the integrity of the medial prefrontal cortex may be crucial for cocaine's action on this neuronal network. In this study, we seek to determine regional selectivity and kinetics of cocaine/NPY interactions. The hypothesis that DA mediates cocaine's action on transcription of the NPY gene will be tested in vivo and in vitro. Moreover, the reduction in NPY may be reflected in cerebrospinal fluid and by an upregulation of NPY receptors. Finally, we will explore the possibilities that the nucleus accumbens, like the medial prefrontal cortex, is necessary for the effect, and that gestational and/or neonatal cocaine exposure affects NPY systems. We propose that NPY may be a sensitive and selective marker for chronic cocaine use. Its reduction may relate to the anxiety and depression associated with cocaine withdrawal in man.